This invention relates to folic acid provided in solid dosage forms. Folic acid (folate) is a water-soluble B vitamin that is widely distributed in foods. In the body, folates function as coenzymes in amino acid metabolism and nucleic acid synthesis. Folate deficiencies lead to impaired cell division and altered protein synthesis.
The physiological benefits of folic acid consumption are numerous. Newborn children of women receiving adequate folic acid in their diet show a lower incidence of spina bifida and anencephaly, both of which are neural tube defects affecting approximately 2500 newborns annually. Adequate intake of folic acid reduces homocysteine levels in the blood, significantly reducing the risk, particularly in men, of heart attack, stroke and peripheral vascular disease. Women with a high intake of folic acid have been shown to be at much reduced risk of developing colorectal adenomas.
The U.S. Public Health Service recommends that women of childbearing age ingest 400 mcg of folic acid per day to reduce their risk of having a child with neural tube defects. The need for women of childbearing age to obtain adequate daily intakes of folic acid, prompted the U.S. Food and Drug Administration (FDA) to issue rules that require fortification of enriched grain products with folic acid. The U.S. Public Health Service also recommends that women obtain folic acid by consuming dietary supplements, such as multivitamin or Vitamin B Complex products.
Dietary sources of folic acid include liver, leafy dark green vegetables, legumes, citrus fruits and juices, and most berries. However, studies indicate that folic acid, in its pure form, is significantly more bioavailable than naturally occurring folate. Approximately three-fourths of the foliate in a typical U.S. diet is present as polyglutamate, a form shown to be about half as bioavailable as crystalline folic acid.
Folic acid is recognized as a significant source of folic acid for a large segment of the population, but recent studies indicate that a number of commercially available dietary supplements do not meet the minimum folic acid dissolution requirements of the USP (U.S. Pharmacopeia). Hoag et al. found that 67% of the folic acid-containing prescription prenatal products tested failed to meet the USP dissolution standard (75% of the labeled amount of folic acid must dissolve in one hour in 900 ml of water at 37° C.) in effect at the time of their research. (Hoag, S W, Ramachandruni H, Shangraw R F., “Failure of prescription prenatal vitamin products to meet USP standards for folic acid dissolution”, J. Am. Pharm. Assoc. 1997; NS37; 397-400).
The FDA has expressed concern over the Hoag study and has also tested a small number of folic acid-containing dietary supplements. They found that some were sub-potent and failed to meet the dissolution standard as well. While no fundamental scientific studies have been conducted to understand the mechanism of folic acid dissolution in dietary supplements, Hoag et al. postulate that raw material properties, manufacturing methods, assay methodologies, and dissolution methodologies might play roles in the poor dissolution performance of certain folic acid containing dietary supplements.
Recently, industry has focused on the dissolution medium as a possible limiting factor in the dissolution test. Folic acid has very limited-solubility in water, approximately 1.6 mcg/ml at 25° C. (The Merck Index, 12th edition). This equates to a solubility limit of about 800 mcg of folic acid in the 900 ml of water that is specified as the dissolution medium for the test. Since the test is performed at 37° C., the actual solubility limit is somewhat higher, but is still only 3-4 times the amount of folic acid contained in most single tablet dosages (200-800 mcg folic acid per tablet). The CRN (Council for Responsible Nutrition), an association of the dietary supplements industry, initiated a study of an alternative dissolution medium, 0.05M citrate buffer. Citrate buffer significantly improved the folic acid dissolution performance of dietary supplements that performed poorly in water. However, for certain products the improvement was not sufficient to consistently meet the USP requirement of greater than 75% of the labeled amount of folic acid dissolved in one hour. Regardless, based on the results of this study, the USP has proposed adopting the 0.05M (pH=6.0) citrate buffer dissolution medium.
While progress has been made on the test methodology side, there is still no guarantee that any individual product formulation will display acceptable folic acid dissolution. In most conventional tablet formulations, folic acid is preblended with other tablet excipients prior to tablet formation to insure uniformity of dosage due to the low level of use (≦400 mcg/dose). Insoluble carriers such as dibasic calcium phosphate are often used in multi-vitamin, multi-mineral formulations as both calcium and phosphorus sources. These materials are resistant to aqueous dissolution and may result in a physical shielding of folic acid from the dissolution medium during the test. It has been hypothesized that folic acid may complex with minerals such as Fe+2, Cu+2 and Zn+2, affecting folic acid solubility.
What is needed is a simple, effective and consistent way to improve the folic acid dissolution performance of dietary supplements in order to enhance the bioavailability of folic acid to the human body. The process described herein produces dietary supplements having significantly improved folio acid dissolution performance. Using that process it is possible to produce dietary supplement solid dosage forms (tablets) from which folic acid dissolves more rapidly than heretofore was possible. With this process one can readily produce a folic acid dosage form from which essentially 100% of the labeled amount of folic acid can dissolve within the time frame of the USP dissolution test (one hour).
In aqueous solutions, folic acid is known to have very limited water solubility and poor chemical stability. In the current process, this limited aqueous solubility is turned into an advantage. Crystalline folic acid can be formulated in combination with common aqueous film coating agents such hydroxypropyl methylcellulose, acacia gum, maltodextrin, soluble starches and pullulan (a naturally occurring polysaccharide derived from Aureobasidium Pullulans yeast). In these formulations, the folic acid concentration is significantly above its aqueous solubility limit and the folic acid is present predominantly as a dispersed solid. In this dispersed state, the folic acid may then be applied by conventional aqueous film coating methods to the outside surface of dietary supplement tablets or caplets so as to form a uniform folic acid containing coating. Folic acid in such an outer coating is released more rapidly than when folic acid is contained in the core tablet, resulting in increased bioavailability.